The present disclosure relates generally to processes for making hydrogel microspheres. More particularly, the present disclosure is directed to processes for making hydrogel microspheres by electrospraying and to processes for making hydrogel microspheres by electrospraying using a solution having a timed gelation.
Hydrogel microspheres of less than 200 μm are powerful tools that have a multitude of applications in the areas of drug delivery, tissue engineering, and biosensors. Hydrogels are a preferred choice because of their tissue-like properties, high water content, ease of fabrication (Lee and Mooney 2001, Hoare and Kohane 2008) and tunable chemical, mechanical and biological characteristics.
Hydrogels composed of polyethylene glycol (PEG) are used often for many biological applications because of its inertness, resistance to protein adsorption, excellent biocompatibility and versatility of PEG macromer chemistry. For encapsulation and delivery of sensitive biological components such as drug, cells, protein, etc., microspheres are a preferred configuration. Encapsulation of bioactive molecules in the semi-permeable membrane formed by the microsphere components not only protects their activity but also simultaneously permits control over their release. Additionally, microspheres can be tailored to be injectable for site-specific delivery and the sustained release of a number of biomolecules.
Numerous methods have been proposed to generate hydrogel microspheres. In general, formation of hydrogel microspheres requires a combination of two mechanisms: droplet generation and a gelation mechanism to with-hold the formed droplet. Droplet generation for making hydrogel microspheres of controlled size and shape can be done using methods such as emulsification precipitation or dispersion and microfluidic channels. In the case of solution dispersion methods such as emulsification, or suspension methods, droplets are generated by mixing immiscible liquids and generating a dispersed phase using various mixing methods such as vortexing, sonication or micronization. However, the high shear stress induced by vortexing, or other mechanical break up methods is harmful for biological applications such as cell or protein encapsulation. Moreover, most of the dispersion-based methods involve the use of either organic solvent or surfactants. Although methods such as microfluidic devices offer a lot of control over process parameters and fabrication characteristics, the devices are very complex in design, and thus, limit widespread applications.
Once a fine dispersion of precursor solution is obtained by any of the above methods, the particles can be cross-linked via covalent and non-covalent crosslinks using a variety of methods. In particular, crosslinking in PEG hydrogel microspheres can be done by chain growth mode based on free radical polymerization, step growth based on conjugate addition, or mixed mode (a combination of chain and step growth). Most of the chemical crosslinking methods or agents employed are harmful to biological molecules which limits their biological application.
It has also been shown that an aqueous based phase separation method may be used to obtain PEG hydrogel microspheres via mixed mode polymerization. Although such a method does not involve use of an organic solvent, an inherent disadvantage is the use of a photointiator and UV light for crosslinking, which are known to be harmful for biological entities and drug stability.
Accordingly, there is a need for a mild process for preparing hydrogel microspheres for bioactive molecule and cell encapsulation. As provided herein, the present disclosure provides a mild process for making hydrogel microspheres by electrospraying to generate fine droplets and subsequently utilizing a controlled, timed gelation for hydrogel formation.